Altered Expression Levels of the Protein Phosphatase 2A ABαC Enzyme Are Associated with Alzheimer Disease Pathology
Abstract
The formation of amyloid-containing senile plaques and tau-rich neurofibrillary tangles are central events in Alzheimer disease (AD) pathogenesis. Significantly, ABalphaC, a major protein phosphatase 2A (PP2A) holoenzyme, specifically binds to and dephosphorylates tau. Deregulation of PP2A results in tau hyperphosphorylation in vivo. Here, we compared the expression levels and distribution of PP2A subunits in various brain regions from autopsy cases of AD and aged controls with or without histological evidence of age-related neurofibrillary degeneration. Immunoblotting analyses revealed that there was a significant reduction in the total amounts of ABalphaC in AD frontal and temporal cortices that matched the decrease in PP2A activity measured in the same brain homogenates. Immunohistochemical studies showed that neuronal ABalphaC expression levels were significantly and selectively decreased in AD-affected regions and in tangle-bearing neurons, but not in AD cerebellum and in non-AD dementias. Reduced neuronal ABalphaC immunoreactivity closely correlated with tangle load, but not plaque burden, suggesting that ABalphaC dysfunction contributes to AD tau pathology. Glial cells within senile plaques were also positive for ABalphaC. Increased glial PP2A immunoreactivity was observed in both AD and non-AD cases and may play a role in the brain's response to general inflammatory processes and amyloidogenesis.
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Increased GSK3β expression and CDK5 activity, decreased expression of PP1 and PP2A, and decreased PP2A activity have been observed in specific brain regions in AD patients.
“In support of this, increased GSK3β expression and CDK5 activity, decreased expression of PP1 and PP2A, and decreased PP2A activity has been observed in specific brain regions in AD patients [148–152].”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [151]
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- Authors
- Sontag, E., Luangpirom, A., Hladik, C., Mudrak, I., Ogris, E., Speciale, S., & White, C. L.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- Khon Kaen University (TH)
- Vienna Biocenter (AT)
- National Institutes of Health (US)
- Corresponding author
- Sontag, Estelle
- Venue
- Journal of Neuropathology & Experimental Neurology
- Publisher
- Oxford University Press (OUP)
- Published
- 2004-04
- Volume
- 63
- Issue
- 4
- Pages
- 287-301
- ISSN
- 0022-3069 (ISSN-L)
- 1554-6578
- OpenAlex
- W189289305
- Cited by
- 228
- References
- 34
- Citations by year
- 2026: 3 · 2025: 7 · 2024: 5 · 2023: 5 · 2022: 5 · 2021: 9 · 2020: 17 · 2019: 9 · 2018: 10 · 2017: 15 · 2016: 10 · 2015: 7 · 2014: 16 · 2013: 9 · 2012: 14
- FWCI
- 5.88
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Neuropathology & Experimental Neurology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Northwestern University
- University of Texas Southwestern Medical Center
- Austrian Science Fund (P 13707)
- National Institutes of Health (AG12300)
- National Institute on Aging (P30AG012300, R01AG018883)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- Alzheimer's disease, protein phosphatase 2A, tau hyperphosphorylation, neurofibrillary tangles, amyloid plaques, amyloid, glial cells, neuroinflammation, amyloidogenesis, frontal and temporal cortex, non-AD dementia
- MeSH terms
- Adult, Aged, Aged, 80 and over, Alzheimer Disease, Brain, Dementia, Female, Humans, Immunohistochemistry, Isoenzymes, Male, Middle Aged, Neuroglia, Neurons, Phosphoprotein Phosphatases, Blotting, Western, Neurofibrillary Tangles, Protein Phosphatase 2, Plaque, Amyloid
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